Neuregulin/ErbB signaling in developmental myelin formation and nerve repair

Myelin is essential for rapid and accurate conduction of electrical impulses by axons in the central and peripheral nervous system (PNS). Myelin is formed in the early postnatal period, and developmental myelination in the PNS depends on axonal signals provided by Nrg1/ErbB receptors. In addition, Nrg1 is required for effective nerve repair and remyelination in adulthood. We discuss here similarities and differences in Nrg1/ErbB functions in developmental myelination and remyelination after nerve injury

CO(2) in the spotlight

Optogenetic techniques have revealed that retrotrapezoid neurons are essential for sensitivity to carbon dioxide

Requirement for beta-catenin in anterior-posterior axis formation in mice

The anterior-posterior axis of the mouse embryo is defined before formation of the primitive streak, and axis specification and subsequent anterior development involves signaling from both embryonic ectoderm and visceral endoderm. Tauhe Wnt signaling pathway is essential for various developmental processes, but a role in anterior-posterior axis formation in the mouse has not been previously established. Beta-catenin is a central player in the Wnt pathway and in cadherin-mediated cell adhesion. We generated beta-catenin-deficient mouse embryos and observed a defect in anterior-posterior axis formation at embryonic day 5.5, as visualized by the absence of Hex and Hesx1 and the mislocation of cerberus-like and Lim1 expression. Subsequently, no mesoderm and head structures are generated. Intercellular adhesion is maintained since plakoglobin substitutes for beta-catenin. Our data demonstrate that beta-catenin function is essential in anterior-posterior axis formation in the mouse, and experiments with chimeric embryos show that this function is required..

Expression and rearrangement of the ROS1 gene in human glioblastoma cells

The human ROS1 gene, which possibly encodes a growth factor receptor, was found to be expressed in human tumor cell lines. In a survey of 45 different human cell lines, we found ROS1 to be expressed in glioblastoma-derived cell lines at high levels and not to be expressed at all, or expressed at very low levels, in the remaining cell lines. The ROS1 gene was present in normal copy numbers in all cell lines that expressed the gene. However, in one particular glioblastoma line, we detected a potentially activating mutation at the ROS1 locus

The dorsal spinal cord and hindbrain: from developmental mechanisms to functional circuits

Neurons of the dorsal hindbrain and spinal cord are central in receiving, processing and relaying sensory perception and participate in the coordination of sensory-motor output. Numerous cellular and molecular mechanisms that underlie neuronal development in both regions of the nervous system are shared. We discuss here the mechanisms that generate neuronal diversity in the dorsal spinal cord and hindbrain, and emphasize similarities in patterning and neuronal specification. Insight into the developmental mechanisms has provided tools that can help to assign functions to small subpopulations of neurons. Hence, novel information on how mechanosensory or pain sensation is encoded under normal and neuropathic conditions has already emerged. Such studies show that the complex neuronal circuits that control perception of somatosensory and viscerosensory stimuli are becoming amenable to investigations

Divergent and conserved roles of Dll1 signaling in development of craniofacial and trunk muscle

Craniofacial and trunk skeletal muscles are evolutionarily distinct and derive from cranial and somitic mesoderm, respectively. Different regulatory hierarchies act upstream of myogenic regulatory factors in cranial and somitic mesoderm, but the same core regulatory network – MyoD, Myf5 and Mrf4 – executes the myogenic differentiation program. Notch signaling controls self-renewal of myogenic progenitors as well as satellite cell homing during formation of trunk muscle, but its role in craniofacial muscles has been little investigated. We show here that the pool of myogenic progenitor cells in craniofacial muscle of Dll1LacZ/Ki mutant mice is depleted in early fetal development, which is accompanied by a major deficit in muscle growth. At the expense of progenitor cells, supernumerary differentiating myoblasts appear transiently and these express MyoD. The progenitor pool in craniofacial muscle of Dll1LacZ/Ki mutants is largely rescued by an additional mutation of MyoD. We conclude from this that Notch exerts its decisive role in craniofacial myogenesis by repression of MyoD. This function is similar to the one previously observed in trunk myogenesis, and is thus conserved in cranial and trunk muscle. However, in cranial mesoderm-derived progenitors, Notch signaling is not required for Pax7 expression and impinges little on the homing of satellite cells. Thus, Dll1 functions in satellite cell homing and Pax7 expression diverge in cranial- and somite-derived muscle

Quantitative proteomics reveals dynamic interaction of c-Jun N-terminal kinase (JNK) with RNA transport granule proteins splicing factor proline- and glutamine-rich (Sfpq) and non-POU domain-containing octamer-binding protein (Nono) during neuronal differentiation

The c-Jun N-terminal kinase (JNK) is an important mediator of physiological and pathophysiological processes in the central nervous system. Importantly, JNK is not only involved in neuronal cell death but also plays a significant role in neuronal differentiation and regeneration. For example, nerve growth factor (NGF) induces JNK-dependent neuronal differentiation in several model systems. The mechanism how JNK mediates neuronal differentiation is not well understood. Here, we employ a proteomic strategy to better characterize the function of JNK during neuronal differentiation. We use SILAC-based quantitative proteomics to identify proteins that interact with JNK in PC12 cells in an NGF-dependent manner. Intriguingly, we find that JNK interacts with neuronal transport granule proteins such as Sfpq and Nono upon NGF treatment. We validate the specificity of these interactions by showing that they are disrupted by a specific peptide inhibitor that blocks the interaction of JNK with its substrates. Immunoprecipitation and western blotting experiments confirm the interaction of JNK1 with Sfpq/Nono and demonstrate that it is RNA dependent. Confocal microscopy and subcellular fractionation indicates that JNK1 associates with neuronal granule proteins in the cytosol of PC12 cells, primary cortical neurons and P19-neuronal cells. Finally, siRNA experiments confirm that Sfpq is necessary for neuronal outgrowth in PC12 cells and that it is most likely acting in the same pathway as JNK. In summary, our data indicate that the interaction of JNK1 with transport granule proteins in the cytosol of differentiating neurons plays an important role during neuronal development

Teashirt 1 (Tshz1) is essential for the development, survival and function of hypoglossal and phrenic motor neurons in mouse

Feeding and breathing are essential motor functions and rely on the activity of hypoglossal and phrenic motor neurons that innervate the tongue and diaphragm, respectively. Little is known about the genetic programs that control the development of these neuronal subtypes. The transcription factor Tshz1 is strongly and persistently expressed in developing hypoglossal and phrenic motor neurons. We used conditional mutation of Tshz1 in the progenitor zone of motor neurons (Tshz1(MNΔ)) to show that Tshz1 is essential for survival and function of hypoglossal and phrenic motor neurons. Hypoglossal and phrenic motor neurons are born in correct numbers, but many die between embryonic day 13.5 and 14.5 in Tshz1(MNΔ) mutant mice. In addition, innervation and electrophysiological properties of phrenic and hypoglossal motor neurons are altered. Severe feeding and breathing problems accompany this developmental deficit. Although motor neuron survival can be rescued by elimination of the pro-apoptotic factor Bax, innervation, feeding and breathing defects persist in Bax(-/-); Tshz1(MNΔ) mutants. We conclude that Tshz1 is an essential transcription factor for the development and physiological function of phrenic and hypoglossal motor neurons

Ontogeny of excitatory spinal neurons processing distinct somatic sensory modalities

Spatial and temporal cues govern the genesis of a diverse array of neurons located in the dorsal spinal cord, including dI1-dI6, dILA, and dILB subtypes, but their physiological functions are poorly understood. Here we generated a new line of conditional knock-out (CKO) mice, in which the homeobox gene Tlx3 was removed in dI5 and dILB cells. In these CKO mice, development of a subset of excitatory neurons located in laminae I and II was impaired, including itch-related GRPR-expressing neurons, PKC{gamma}-expressing neurons, and neurons expressing three neuropeptide genes: somatostatin, preprotachykinin 1, and the gastrin-releasing peptide. These CKO mice displayed marked deficits in generating nocifensive motor behaviors evoked by a range of pain-related or itch-related stimuli. The mutants also failed to exhibit escape response evoked by dynamic mechanical stimuli but retained the ability to sense innocuous cooling and/or warm. Thus, our studies provide new insight into the ontogeny of spinal neurons processing distinct sensory modalities

Sustained MAPK/ERK activation in adult Schwann cells impairs nerve repair

The MAPK/ERK pathway has a critical role in PNS development. It is required for Schwann cell (SC) differentiation and myelination; sustained embryonic MAPK/ERK activation in SCs enhances myelin growth overcoming signals that normally end myelination. Excess activation of this pathway can be maladaptive as in adulthood acute strong activation of MAPK/ERK has been shown to cause SC dedifferentiation and demyelination. We used a mouse model (including male and female animals) in which gain of function Mek1DD allele produces sustained MAPK/ERK activation in adult SCs and we determined the impact of such activation on nerve repair. In the uninjured nerve, MAPK/ERK activation neither impaired myelin nor did it re-activate myelination. However, in the injured nerve it was detrimental and resulted in delayed repair and functional recovery. In the early phase of injury the rate of myelin clearance was faster. Four weeks following injury, when nerve repair is normally advanced, myelinated axons of Mek1DD mutants demonstrated higher rates of myelin decompaction, a reduced number of Cajal bands and decreased internodal length. We noted the presence of abnormal Remak bundles with long SCs processes and reduced numbers of C-fibres/Remak bundle. Both the total number of regenerating axons and the intra-epidermal nerve fibres density in the skin were reduced. Sustained activation of MAPK/ERK in adult SCs is therefore deleterious to successful nerve repair, emphasising the differences in the signalling processes coordinating nerve development and repair. Our results also underline the key role of SCs in axon regeneration and successful target einnervation.SIGNIFICANCE STATEMENTThe MAPK/ERK pathway promotes developmental myelination and its sustained activation in SCs induced continuous myelin growth, compensating for the absence of essential myelination signals. However, the strength of activation is fundamental because acute strong induction of MAPK/ERK in adulthood induces demyelination. What has been unknown is the effect of a mild but sustained MAPK/ERK activation in SCs on nerve repair in adulthood. This promoted myelin clearance but led to abnormalities in non-myelinating and myelinating SCs in the later phases of nerve repair, resulting in slowed axon regeneration, cutaneous reinnervation and functional recovery. Our results emphasise the distinct role of the MAPK/ERK pathway in developmental myelination versus remyelination and the importance of signalling between SCs and axons for successful axon regeneration